Process for preparing certain substituted caprolactams

ABSTRACT

The present invention relates to an improved process for preparing certain substituted caprolactam compounds which comprises acylating an aminocaprolactam compound with a lactone compound in the presence of a weak base and a polar, organic solvent, and hydrolyzing the resultant diamide compound in a mixture of solvents to obtain the desired caprolactam compound.

[0001] This application claims the benefit of provisional applicationNo. 60/275,099 filed Mar. 12, 2001, the contents of which areincorporated herein by reference.

[0002] The present invention relates to a process for preparing certainsubstituted caprolactams.

FIELD OF INVENTION

[0003] The present invention relates to the area of syntheticmethodology and, more particularly, to a process for preparing certainsubstituted caprolactams.

BACKGROUND OF THE INVENTION

[0004] Marine organisms provide a potential source of biologicallyactive compounds, including compounds which are potentially useful asanti-tumor agents. For example, U.S. Pat. No. 4,831,135 disclosescertain bengamide compounds which were isolated by extraction from theJaspidae marine sponge family native to the waters surrounding the Fijiislands and which exhibit anti-tumor, antibiotic and anthelminticproperties. In fact, the chemistry of Jaspidae sponges has been thesubject of numerous publications over the last 10 years. More recently,WO 00/29382 discloses certain analogs of the bengamides disclosed in theabove-mentioned U.S. patent, which analogs are useful in treatingvarious types of tumors. Although WO 00/29382 discloses a suitableprocess for preparing all of the analogs disclosed therein, theirever-growing importance has resulted in a need for a more practical andcommercially acceptable synthesis.

SUMMARY OF THE INVENTION

[0005] The present invention relates to an improved process forpreparing certain substituted caprolactams. The process of the presentinvention is believed to be more practical and commercially acceptablethan the process disclosed in WO 00/29382 since it is carried out undermore mild reaction conditions and results in an easier work-up of thedesired compounds. More particularly, the process of the instantinvention involves the acylation of an aminocaprolactam compound with alactone compound in the presence of a weak base and a polar, organicsolvent, and the hydrolysis of the 1,3-dioxane group of the resultingdiamide compound to obtain the desired substituted caprolactam compound.

DETAILED DESCRIPTION OF THE INVENTION

[0006] The present invention relates to an improved process forpreparing certain substituted caprolactams of formula I:

[0007] where

[0008] R₁ is (C₁₋₆)alkyl or (C₃₋₆)cycloalkyl;

[0009] R₂ is hydrogen or (C₁₋₆)alkyl;

[0010] X is (C₁₋₁₂) alkylene; (C₂₋₁₂) alkenylene; or (C₂₋₁₂) alkynylene;

[0011] m is 0 or 1; and

[0012] R₃ is (C₃₋₈)cycloalkyl; or an aromatic ring system selected fromII, III, IV and V:

[0013]  where

[0014] R₄ is hydrogen, chloro, or methoxy;

[0015] R₅ is hydrogen, chloro, (C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy; and Z isoxygen, sulfur, N—H, or N—CH₃;

[0016] or a pharmaceutically acceptable acid addition salt thereof,where possible. More particularly, the substituted caprolactam compoundsof formula I are prepared by a two-step process as depicted below:

[0017] where each R₁, R₂, X, m and R₃ is as defined above.

[0018] As to the individual steps, Step A involves the acylation of anaminocaprolactam compound of formula VI , or an acid addition saltthereof, with a lactone compound of formula VII to obtain a diamidecompound of formula VIII. The acylation is conducted in the presenceof: 1) a weak base, preferably a carboxylate salt such as sodium2-ethylhexanoate, and 2) a polar, organic solvent, preferably a cyclicether such as tetrahydrofuran, at a temperature of between 0° C. and 50°C., preferably at 25° C., for a period of between 1 hour and 7 days,preferably for 20 hours.

[0019] Step B concerns the hydrolysis of the 1,3-dioxane group common toa diamide compound of formula VIII, to obtain the desired substitutedcaprolactam compound of formula I. The hydrolysis is typically carriedout by dissolving the diamide in a mixture of solvents consisting of 1)a protic acid, preferably an organic acid such as trifluoroacetic acid,or an inorganic acid such as hydrochloric acid; 2) a protic solvent,preferably water, and 3) an inert organic solvent, preferably a cyclicether such as tetrahydrofuran, at a temperature of between 0° C. and 50°C. for a period of between 1 hour and 5 hours.

[0020] The aminocaprolactam compounds of formula VI and the lactonecompounds of formula VII may be prepared as described in WO 00/29382. Asindicated above, an acid addition salt of a compound of formula VI maybe utilized in Step A. For example, the compound of Example 1g) of WO00/29382 can be reacted with HCl to form the corresponding hydrochloridesalt form of the compound of Example 1 h) of WO 00/29382.

[0021] Although the diamide compound that is obtained in Step Adescribed above may, if desired, be purified by conventional techniquessuch as recrystallization, the crude diamide compound is advantageouslyemployed in Step B described above without purification. The free baseof the compound of formula I may, if desired, be converted into the acidaddition salt form, where possible. The acid addition salts of thecompounds of formula I may be those of pharmaceutically acceptableorganic or inorganic acids. Although the preferred acid addition saltsare those of hydrochloric and methanesulfonic acid, salts of sulfuric,phosphoric, citric, fumaric, maleic, benzoic, benzenesulfonic, succinic,tartaric, lactic and acetic acid are also contemplated. Such salts maybe obtained by reacting the free base of a compound of formula I withthe corresponding acid to obtain the desired acid addition salt form.

[0022] As is evident to those skilled in the art, the substitutedcaprolactam compounds of formula I contain asymmetric carbon atoms. Itshould be understood, therefore, that the individual stereoisomers arecontemplated as being included within the scope of the invention.

[0023] Preferred substituted caprolactams which may be prepared by theprocess of this invention are those of formula I where

[0024] R₁ is (C₁₋₆)alkyl;

[0025] R₂ is hydrogen or (C₁₋₄)alkyl;

[0026] X is (C₁₋₆)alkylene or (C₂₋₆)alkynylene;

[0027] m is 0 or 1; and

[0028] R₃ is (C₃₋₈)cycloalkyl; or an aromatic ring system selected fromII, III, IV and V where

[0029] R₄ is hydrogen, chloro, or methoxy; and

[0030] R₅ is hydrogen, chloro, (C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy; and Z isoxygen, sulfur, N—H, or N—CH₃;

[0031] or a pharmaceutically acceptable acid addition salt thereof,where possible.

[0032] More preferred substituted caprolactams which may be prepared bythe process of this invention are those of formula I where

[0033] R₁ is i-propyl or t-butyl;

[0034] R₂ is hydrogen or methyl;

[0035] m is 0 or 1;

[0036] X is (C₁₋₆) alkylene; and

[0037] R₃ is (C₅₋₇)cycloalkyl; or an aromatic ring system selected fromIIa and V:

[0038] where

[0039] R₄′ is in the meta position and is hydrogen or chloro; and

[0040] R_(5′) is in the para position and is hydrogen, chloro,(C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy; or a pharmaceutically acceptable acidaddition salt thereof, where possible. Even more preferred substitutedcaprolactam compounds which may be prepared by the process of thisinvention are those of formula I where

[0041] R₁ is i-propyl or t-butyl;

[0042] R₂ is hydrogen or methyl;

[0043] m is 0 or 1;

[0044] X is methylene or ethylene; and

[0045] R₃ is (C₅₋₇)cycloalkyl, phenyl, 3,4-dichlorophenyl,4-methoxyphenyl, 4-n-decylphenyl, 4-n-decyloxyphenyl or 3-pyridyl;

[0046] with the proviso that when m is 0, R₃ is (C₅₋₇)cycloalkyl,4-n-decylphenyl or 4-n-decyloxyphenyl;

[0047] or a pharmaceutically acceptable acid addition salt thereof,where possible.

[0048] The following examples are for purposes of illustration only andare not intended to limit in any way the scope of the instant invention.

EXAMPLE 1(6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-O-methyl-3,5-O-(1-methylethylidene)-gulo-non-6-enonic acid lactone

[0049] Following essentially the procedures of Examples 1a)-1e) of WO00/29382, the title compound is obtained as a white crystalline solid.

EXAMPLE 2 (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one

[0050] Following essentially the procedures of Examples 1f) and 1g) ofWO 00/29382, the title compound is obtained as a white solid.

EXAMPLE 3 (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclohexylcorbonyl)oxy-2H-azepin-3-3-yl]non-6-enamide.

[0051] a) Preparation of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide.

[0052] To a stirred solution of ethyl acetate (3 L) and HCl gas (225 g,6.2 mol) at room temperature is added, portionwise, 300 g (846 mmol) ofthe compound of Example 2. The reaction is stirred at room temperaturefor 6 hours. The resulting precipitate is filtered and the solid iswashed with ethyl acetate (1.2 L). The solid is dried to give 246 g(98%) of (3S,6R)-3-aminohexahydro-6-cyclohexanecarbonyl)oxy-2H-azepin-2-one.HCl whichis used directly in the next step. A solution consisting of 100 g (352mmol) of the compound of Example 1, 112.5 g (387 mmol) of 3S,6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one.HCl,sodium 2-ethylhexanoate (116 g, 700 mmol) and tetrahydrofuran (1.75 L)is stirred at room temperature for 20 hours. Water (350 mL) is thenadded to the mixture. After stirring for an additional 30 minutes,heptane (3.5 L) is added. The mixture is then stirred for 3 hours, thencooled to 2° C. and then stirred for an additional 2 hours. The mixtureis filtered through a polypropylene filter. The solid that remains iswashed with water (200 mL) and heptane (800 mL). The solid is then driedto give 166 g (88%) of the desired compound as a white solid.

[0053] b) Preparation of the title compound.

[0054] To a stirred solution of trifluoroacetic acid (10 ml),tetrahydrofuran (10 ml) and water (5 ml) at 0° C. is added, in oneportion, 3.8 g (7.1 mmol) of the compound prepared in a) above. Thereaction is stirred at 0° C. for 30 minutes, concentrated via rotaryevaporation (bath temperature <20° C), mixed with saturated NH₄HCO₃ (5mL) and stirred for 15 minutes. The mixture is concentrated in vacuo andchromatographed (2% methanol-CH₂Cl₂) to give a white solid with H₂Osolubility of 3.7 mg/mL. This material is further purified usingpreparative hplc (reverse phase eluted with 90% CH₃CN-water) to give 2.9g (82.4%) of the title compound as a white solid, m.p. 79-80° C.

[0055] b¹) Alternate preparation of the title compound.

[0056] To a cooled (22° C.) solution of tetrahydrofuran (100 mL) and 1Nhydrochloric acid (200 mL) is added 10 g (28.2 mmol) of the compound ofExample 2. The resultant mixture is stirred for 3 hours at 22° C., afterwhich time it is cooled to 5° C. The reaction mixture is thenneutralized with an aqueous 5N sodium hydroxide solution (40 mL) to a pHof 7. Sodium chloride (77 g, 1.32 mol) is then added to the resultantmixture, after which time it is stirred for 30 minutes at 22° C. Theresultant product is then extracted into ethyl acetate (100 mL) and thesolvents are removed under vacuum. The residue is then re-dissolved intert-butyl methyl ether (40 mL) at 50° C., crystallized from thesolution at 20° C.-0° C., collected by filtration and washed withtert-butyl methyl ether (20 mL). After drying, 8 g of the crude productis obtained. The crude product is further purified by recrystallizationfrom a mixture of ethanol (10 mL) and water (40 mL) at 0° C. to give 7.2g of the title compound as a white solid.

What is claimed is:
 1. A process for preparing a caprolactam compound offormula I

where R₁ is (C₁₋₆)alkyl or (C₃₋₆)cycloalkyl; R₂ is hydrogen or(C₁₋₆)alkyl; X is (C₁₋₁₂) alkylene; (C₂₋₁₂) alkenylene; or (C₂₋₁₂)alkynylene; m is 0 or 1; and R₃ is (C₃₋₈)cycloalkyl; or an aromatic ringsystem selected from II, III, IV and V:

 where R₄ is hydrogen, chloro, or methoxy; R₅ is hydrogen, chloro,(C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy; and Z is oxygen, sulfur, N—H, or N—CH₃;or a pharmaceutically acceptable acid addition salt thereof, wherepossible, which process comprises, in a first step, acylating anaminocaprolactam compound of formula VI

or an acid addition salt thereof, with a lactone compound of formula VII

in the presence of: 1) a weak base; and 2) a polar organic solvent toobtain a diamide compound of formula VIII

where each of R₁, R₂, X, m and R₃ is as defined above and, in a secondstep, hydrolyzing the diamide compound obtained in the first step bydissolving it in a mixture of solvents to obtain the desired caprolactamcompound of formula I.
 2. A process according to claim 1 wherein theacylation step is carried out in the presence of: 1) a carboxylate salt;and 2) a cyclic ether.
 3. A process according to claim 2 wherein theacylation step is carried out in the presence of: 1) sodium2-ethylhexanoate; and 2) tetrahydrofuran.
 4. A process according toclaim 3 wherein the acylation step is carried out at a temperature ofbetween 0° and 50° C.
 5. A process according to claim 1 wherein thehydrolysis step is carried out by dissolving the diamide compoundobtained in the first step in a mixture of solvents consisting of: 1) aprotic acid; 2) a protic solvent; and 3) an inert, organic solvent.
 6. Aprocess according to claim 5 wherein the mixture of solvents consistsof: 1) an organic acid; 2) water; and 3) a cyclic ether.
 7. A processaccording to claim 6 wherein the mixture of solvents consists of: 1)trifluoroacetic acid; 2) water; and 3) tetrahydrofuran.
 8. A processaccording to claim 5 wherein the hydrolysis step is carried out at atemperature of between 0° and 50° C.
 9. A process according to claim 5wherein the mixture of solvents consists of: 1) an inorganic acid; 2)water; and 3) a cyclic ether.
 10. A process according to claim 9 whereinthe mixture of solvents consists of: 1) hydrochloric acid; 2) water; and3) tetrahydrofuran.